Inflammation and rejection are the principal obstacles to the use of pancreatic islet cell transplantation for the treatment of insulin-dependent diabetes mellitus. Current treatment regimens have limited efficacy and substantial toxicity. A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has now been implicated in the pathogenesis of pancreatic islet cell allograft rejection. PARS activation induces AP-1 dependent pro-inflammatory gene expression and consumes NAD, resulting in ATP depletion and cellular energetics failure. In this proposal, we present experimental evidence that pharmacologic inhibition of PARS activity and genetic ablation of the PARS gene have potent anti-inflammatory effects and prolong allograft survival. Inotek is developing a highly potent, specific, non-toxic, and proprietary PARS inhibitor, 5-iodo-6-amino-1,2-benzopyrone (INH2BP). The specific aims of the present proposal are to determine the benefit of INH2BP in the prevention of cellular injury and dysfunction in the early and late phases of graft failure in an experimental model of pancreatic islet cell transplantation. The demonstration that INH2BP prevents tissue injury and prolongs graft survival and functions in this model would represent a breakthrough in the design of novel anti-inflammatory regimens for islet transplant rejection and would justify its further commercial development. PROPOSED COMMERCIAL APPLICATION: The domestic market for a novel, effective therapy to prevent pancreatic islet cell rejection is estimated at $500 million per annum. Global markets are estimated at $2 billion. Current market entrants have substantial toxicity. INH2BP may represent the first highly potent and successful candidate therapy; funding of SBIR Phase I and II will allow for market entry in 3.5 years.